Vascular reconstructions with synthetic prostheses fail because of their thrombogenic surfaces and, at late times, because of excessive neointimal thickening. The overall objectives of this proposal are to define conditions optimal for the spontaneous formation of a non-thrombogenic endothelialized surface and to define what factors regulate subsequent neointimal smooth muscle cell (SMC) growth in a baboon model of synthetic arterial graft failure. Our recent studies on the healing of polytetrafluorethylene (PTFE) grafts suggest that an endothelialized surface can be induced by altering graft porosity and allowing transmural capillary ingrowth. We have also shown that late neointimal thickening is the consequence of SMC proliferation underneath an intact endothelium. We now plan to investigate the role of graft porosity, structure, and length in the development of the endothelial layer and subsequent intimal thickening. We will attempt to limit SMC growth in the intima with heparin (a direct inhibitor of SMC growth). Finally, we will explore the hypothesis that vascular wall cells (endothelium and SMC) themselves regulate SMC growth in the graft intima by the production of growth factor. These studies have potential clinical application since heparin-like drugs may prove useful in preventing the failure of vascular reconstructions caused by exuberant myointimal thickening. Furthermore, such studies may shed light on the in vivo mechanisms of smooth muscle growth control in healing vascular grafts. Light and electron microscopy, cell culture, thymidine autoradiography, Northern blot analysis, and in situ hybridization will be used in these experiments.